Cancer is a complex genetic disease. In the post-genomic era, new initiatives are underway to completely understand the genetic makeup of a patient's tumor to personalize treatment. While many important tumor suppressors and oncogenes have been identified in this manner, it is important to recognize that many genes that are driver mutations in cancer are members of gene families. The existence of redundant functions in gene families has made diseases like cancer challenging to treat and cure due to the limited knowledge about the functions of each gene within the family. The p53 family is one such gene family and is the focus of the research in my laboratory. Despite long-standing knowledge that the p53 function is frequently altered in cancer, p53 has persisted as an undruggable target because of its function as a transcription factor and because it lacks an enzymatic activity that can be readily inhibited. In our view, this failure is directly tied to inadequate understanding of how the p53 family functions as a whole. In an effort to identify novel ways of targeting p53 in cancer, my laboratory has been focused on understanding the interrelated biological functions of the p53 family, which includes the p63 and p73 genes. We have made great strides in understanding and identifying novel functions for p63 and p73 in metastasis (Su et al., Nature 2010), stem cell maintenance (Su et al., Cell Stem Cell 2009; Chakravarti et al., PNAS 2014), and metabolism (Su et al., Cell Metabolism 2012) using novel mouse models generated in my laboratory. These mouse models have also revealed novel functions of p63 and p73 in tumor metabolism and have allowed us to manipulate particular isoforms of p63 and p73 to therapeutically target p53 deficient and mutant tumors (Venkatanarayan et al., Nature 2014, in press)(See Appendix). In this proposal, we aim to further use these mouse models and several novel high throughput modalities to understand the biological functions of non-coding RNA regulated by the p53 family in cancer metastasis and tumor metabolism. We will integrate this knowledge in an effort to rationally target the p53 pathway using non-coding RNAs. Discoveries made to target the p53 pathway can be potentially applied more broadly to other undruggable targets. Support through the R35 mechanism will greatly facilitate this large undertaking that would not otherwise be possible.